Costimulation Light: Activation of CD4+ T Cells with CD80 or CD86 Rather Than Anti-CD28 Leads to a Th2 Cytokine Profile

Broeren, Chris P. M.; Gray, Gary S.; Carreño, Beatriz M.; June, Carl H.

doi:10.4049/jimmunol.165.12.6908

Cited by 41 publications

(42 citation statements)

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“…Manipulation of the culture conditions can enhance Th1 or Th2 CD4 cell functions. 21,74,75 We have recently completed a phase I study of autologous SCT followed by infusions of ex vivo expanded costimulated T cells for patients with relapsed or refractory NHL and determined that (1) the administration of up to 1 Â 10 10 CD3 þ cells is safe and feasible and (2) these cells result in both a dosedependent increase in day 30 lymphocyte counts, an increase in Th1 cell function as assessed by interferon-g secretion, and a delayed leukocytosis. 21 Larger studies will determine if these effects translate into improved outcomes after autologous SCT.…”

Section: Enhanced Immune Reconstitution Though Adoptive Transfer Of Tmentioning

confidence: 99%

T-cell reconstitution and expansion after hematopoietic stem cell transplantation: ‘T’ it up!

Porter

June

2005

Bone Marrow Transplant

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Summary:Adoptive immunotherapy is the isolation and infusion of antigen-specific or nonspecific lymphocytes. Adoptive therapy with T cells may have a role in replacing, repairing, or enhancing immune function damaged by cytotoxic therapies, and rapid lymphocyte recovery may improve outcome after autologous and allogeneic stem cell transplantation (SCT). Recently, a plethora of information on the basic mechanisms of T-cell biology and regulation of cellular immune responses has emerged, permitting the development of new forms of adoptive cell therapy. Efficient ex vivo culture method for T-cell subsets affords the possibility of adoptive transfer of T cells engineered with enhanced capacity for central memory, effector cytotoxicity, Th1, Th2, veto cell, and T regulatory functions. Studies show that homeostatic Tcell proliferation is important for effective adoptive immunotherapy and pretreatment with chemotherapy may enhance the effects of infused T cells. Replicative senescence, in part due to telomere erosion, likely limits successful adoptive immunotherapy, though it may be possible to maintain T-cell pools by enforced expression of telomerase. Clinical trials now demonstrate that it is possible to enhance immune reconstitution after SCT with cytokines or infusions of ex vivo costimulated expanded T cells. These data all support the premise that adoptive therapy can accelerate reconstitution of cellular immunity with enhanced antitumor effects following SCT. Bone Marrow Transplantation (2005) 35, 935-942.

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Section: Enhanced Immune Reconstitution Though Adoptive Transfer Of Tmentioning

confidence: 99%

T-cell reconstitution and expansion after hematopoietic stem cell transplantation: ‘T’ it up!

Porter

June

2005

Bone Marrow Transplant

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“…This method turned out to be a very efficient method to stimulate T cells since transduction with retrovirus, which requires T cell division, resulted in up to 80% transduced T cells. Stimulation with anti-CD3/anti-CD28 mAbs resulted in a higher IFN-␥ response over an IL-4 response, which is indicative of T h 1 cells as has been described before (Broeren et al, 2000). However, this phenotype could be skewed to a more pronounced T h 1 phenotype or to a T h 2 phenotype when either IL-12p70 and anti-IL-4 mAb or IL-4 and anti-IFN-␥ mAb were present during T cell activation, respectively.…”

Section: Discussionmentioning

confidence: 88%

“…To genetically modify T cells using a retroviral system we activated T cells with anti-CD3/anti-CD28 mAb-conjugated magnetic beads (Broeren et al, 2000). Rheumatic joints contain clonally expanded T cell populations.…”

Section: Discussionmentioning

confidence: 99%

“…To effectively induce T cell proliferation without the need for antigenic peptides and to circumvent the need to separate T cells from antigen presenting cells after stimulation and transduction we choose an APC-free T cell stimulation system. For this we used magnetic beads coated with anti-CD3 mAb and superagonistic anti-CD28 mAb as described earlier (Broeren et al, 2000). Using this protocol, numbers of T cells that were transduced ranged, depending on the transgene, from 55-80% of the T cells as analyzed by flow cytometry of GFP expression (Fig.…”

Section: Generation Of Genetic Constructs and Transduction Of Cd4 + Cmentioning

confidence: 99%

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Cartilage proteoglycan-specific T cells as vectors of immunomodulatory biologicals in chronic proteoglycan-induced arthritis

Guichelaar

Brink

Kooten

et al. 2008

Molecular Immunology

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a b s t r a c tSystemic administration of agents that neutralize or antagonize T h 1-mediated pro-inflammatory responses has been demonstrated to ameliorate inflammation in chronic autoimmune disease. However, systemic administration of such immunosuppressive biologicals causes serious side effects and has only limited success. To minimize these side effects, autoantigen-specific lymphocytes have been proposed as a carrier to deliver immunosuppressive agents to sites of inflammation. Here we studied the effects of primary cartilage proteoglycan-specific CD4 + T cells that were transduced using an efficient method of viral transduction with active genes encoding IL-1␤ receptor antagonist, soluble TNF-␣ receptor-Ig, IL-4 or IL-10 in chronic proteoglycan-induced arthritis in mice. This is the first study describing such gene therapy using primary CD4 + T cells in a chronic arthritis. Moreover, the impact of proteoglycan-specific T h 1, T h 2 or naïve T cells was studied. Although proteoglycan-TCR transgenic CD4 + T cells can transfer arthritis to lymphopenic recipients, none of the proteoglycan-TCR transgenic T cell phenotypes that were tested induced worsening of arthritis in wild type hosts. Proteoglycan-specific T cells ameliorated arthritis when expressing the transduced IL-10 gene, and not when expressing the other transgenes/phenotypes. Although all of the tested biologicals can suppress in a wide range of different inflammatory disorders, especially IL-10 would therefore serve as a promising candidate to be used in cellular gene therapy for chronic arthritis.

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“…A previous study (26) established that the B7.2-Ig fusion protein is effective for costimulation in vitro of anti-CD3-triggered T cells by stimulating CD28 molecules. Regarding sensitization in vivo of antitumor T cells in tumor-bearing mice, our earlier studies showed that APC pick up and present tumor-Ags to prime tumorreactive T cells (5,27,28).…”

Section: Systemic Adminstration Of B72-ig Fusion Proteins Induces Comentioning

confidence: 99%

Induction of Tumor Regression by Administration of B7-Ig Fusion Proteins: Mediation by Type 2 CD8+ T Cells and Dependence on IL-4 Production

Yamaguchi

Hiraoka

Mukai

et al. 2004

The Journal of Immunology

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CD28 signals contribute to either type 1 or type 2 T cell differentiation. Here, we show that administration of B7.2-Ig fusion proteins to tumor-bearing mice induces tumor regression by promoting the differentiation of antitumor type 2 CD8+ effector T cells along with IL-4 production. B7.2-Ig-mediated regression was not induced in IL-4−/− and STAT6−/− mice. However, it was elicited in IFN-γ−/− and STAT4−/− mice. By contrast, IL-12-induced tumor regression occurred in IL-4−/− and STAT6−/− mice, but not in IFN-γ−/− and STAT4−/− mice. Moreover, B7.2-Ig treatment was effective in a tumor model not responsive to IL-12. B7.2-Ig administration elicited elevated levels of IL-4 production. Tumor regression was predominantly mediated by CD8+ T cells, although the induction of these effector cells required CD4+ T cells. Tumor regression induced by CD8+ T cells alone was inhibited by neutralizing the IL-4 produced during B7.2-Ig treatment. Thus, these results indicate that stimulation in vivo of CD28 with B7.2-Ig in tumor-bearing mice results in enhanced induction of antitumor type 2 CD8+ T cells (Tc2) leading to Tc2-mediated tumor regression.

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Costimulation Light: Activation of CD4+ T Cells with CD80 or CD86 Rather Than Anti-CD28 Leads to a Th2 Cytokine Profile

Cited by 41 publications

References 50 publications

T-cell reconstitution and expansion after hematopoietic stem cell transplantation: ‘T’ it up!

T-cell reconstitution and expansion after hematopoietic stem cell transplantation: ‘T’ it up!

Cartilage proteoglycan-specific T cells as vectors of immunomodulatory biologicals in chronic proteoglycan-induced arthritis

Induction of Tumor Regression by Administration of B7-Ig Fusion Proteins: Mediation by Type 2 CD8+ T Cells and Dependence on IL-4 Production

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